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Biomedical subjects

L Binderup

Publications and source records attributed to L Binderup.

At least 55 records · Page 3Linked to original sources
PubMed1997

CB1093, a novel vitamin D analog; effects on differentiation and clonal growth on HL-60 and de novo leukemia cells.

We studied the effects of a novel vitamin D analog CB1093, EB1089 (one of the most antileukemic analogs yet) and 1 alpha,25(OH)2D3 both on HL-60 cells and cells from 13 AML patients. Differentiation was measured both by induction of superoxide production and non-specific esterase. Cell proliferation was assessed by colony assay and 3H-thymidine incorporation. The effect on serum calcium was measured in rats. The CB1093 proved to be the most efficient of the analogs tested so far, both in inducing differentiation and in inhibiting proliferation. This, combined with its low hypercalcemic effect shown here, makes it a promising candidate for preclinical animal studies.

Animals↗
PubMed1997

Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist.

The present paper describes the structural modifications leading to the discovery of a new series of quinoline-containing cys-LT1 receptor (LTD4 receptor) antagonists. A structural optimization with respect to the in vitro receptor binding, the in vivo brochoconstriction, and the toxicological effect in the form of peroxisomal proliferation was performed in order to achieve the target compound OT4003. OT4003 ((S)-(+)-E-2-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxyl++ +-hexanoic acid) was found to be a potent and selective inhibitor of [3H]LTD4 specific binding to guinea pig lung membranes (IC50 2.4 +/- 1.0 nM), and also a potent, orally active, antagonist of LTD4 induced bronchoconstriction in guinea pigs [ED50 0.14 (ED16 0.1-ED84 0.4) mg/kg; 4 h pretreatment]. The enantiomerically pure OT4003 was prepared using a short convergent synthesis, including an enzymatic resolution step.

Administration, Oral↗
PubMed1997

Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro.

The GER human pancreatic carcinoma cell line possesses receptors for 1,25-dihydroxyvitamin D3. We report that the vitamin D analogue EB 1089 inhibits the growth of these cells in vitro and when grown as tumour xenografts in immunodeficient mice. Tumour-bearing mice were given EB 1089 at a dose of 5 microg kg(-1) body weight i.p. thrice weekly for 4-6 weeks. Tumour growth was significantly inhibited in treated animals compared with controls in the absence of hypercalcaemia. These findings may have therapeutic implications in pancreatic cancer.

Adenocarcinoma↗
PubMed1997

Proliferation and differentiation of cultured human keratinocytes is modulated by 1,25(OH)2D3 and synthetic vitamin D3 analogues in a cell density-, calcium- and serum-dependent manner.

The natural form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) decreases proliferation and promotes terminal differentiation of cultured human epidermal keratinocytes. The purpose of this study was to find out to what extent the culture conditions determine the sensitivity of keratinocytes to 1,25(OH)2D3 and synthetic vitamin D analogues. Human keratinocytes were grown in microplates. Cell proliferation (MTT-assay) and differentiation (quantity of transglutaminase type I) were measured consecutively in the same monolayer. When vitamin D3 analogues were added to 50-60% confluent keratinocytes grown in serum-free keratinocyte growth medium with 0.09 mM Ca2+, stimulation of the proliferation was either minimal or non-existent, while differentiation was unaffected or slightly inhibited. There was no difference in the sensitivity to 1,25(OH)2D3 and the vitamin D3 analogues. When 1,25(OH)2D3 was added to less confluent keratinocytes (30%) a marked antiproliferative effect was observed. Addition of 3% charcoal stripped foetal calf serum further enhanced the antiproliferative effect of 1,25(OH)2D3, and a difference in the sensitivity of the vitamin D3 analogues was noted. If, finally, the Ca2+ concentration was raised to 0.3 mM, 1,25(OH)2D3 and the vitamin D3 analogues stimulated differentiation. Also, a biphasic effect on proliferation occurred: stimulation at low vitamin D concentrations and inhibition at higher concentrations. Furthermore, keratinocytes became more sensitive to the synthetic vitamin D3 analogues than to 1,25(OH)2D3: KH1060 > EB1089 > GS1500 > or = EB1213 > calcipotriol > 1,25(OH)2D3. For all compounds tested differentiation occurred at concentrations 10 to 30 times lower than for proliferation. These results indicate that the sensitivity to vitamin D3 analogues as well as the direction of the response to vitamin D3 analogues is dependent on the keratinocyte density, the availability of serum and Ca2+ concentrations.

Antibodies, Monoclonal↗
PubMed1997

The rat subcutaneous air sac model: a new and simple method for in vivo screening of antiangiogenesis.

An experimental rat model, the Subcutaneous Air Sac (SAS) model, was developed to provide an animal model in which neo-vascularization can be easily assessed in situ and quantified using a radiolabelled plasma marker. The SAS model was designed to replace a previous model where neovascularization was induced by chemical injury of rat or rabbit cornea or by implantation of tumour cells intracorneally, a methodology which is believed to cause severe pain to the animals. In the SAS model the air sac replaces the cornea as a transparent avascular substratum in which vascularization can be observed. The air sac is induced by injection of air subcutaneously on the back of the animal. After 8 to 10 days a sufficient air sac has been established. The animal is anaesthesized and by a minor operation the cellulose sponge is implanted upon the air sac under the skin. The vasoproliferative effect of the cellulose sponge causes formation of new vessels which are macroscopically visible 10 days after implantation. The ability of the in vivo SAS model to show an antiangiogenic effect of a systemically applied test compound was investigated using the fumagillin analogue TNP-470 (ochloro-acetylcarbamoyl)-fumagillol) as a positive control at dose levels of 0, 1, 2.5, 5 and 10 mg/kg/day given subcutaneously for 10 days. The neo-angiogenesis was scored both in situ using a subjective point system and by measuring the 125I-activity of the implant and the membrane after an intravenous injection of 125I-labelled antibodies. The neo-angiogenesis was reduced by approximately 45-50% in animals treated with 5 or 10 mg/kg/day of TNP-470 compared to animals treated with the vehicle. The animals treated with 10 mg/kg/day TNP-470 showed signs of toxicity. The SAS model is considered highly relevant for in vivo testing of potential antiangiogenic drugs on humane grounds. The high reproducibility, the low cost and the technical simplicity of the method makes it attractive.

Air↗
PubMed1996

High-affinity nuclear receptor binding of 20-epi analogues of 1,25-dihydroxyvitamin D3 correlates well with gene activation.

The hormone 1,25-dihydroxyvitamin D3 (VD) has the potential for clinical use in several diseases, such as cancer, osteoporosis, and psoriasis. The action of VD is mediated by primary responding genes that contain in their promoter region a binding site for the transcription factor VDR. Most of the known VD response elements are formed by a direct repeat of two hexameric core binding motifs spaced by three nucleotides (DR3) bound by a heterodimer of VDR and the retinoid X receptor (RXR). Various VD analogues have been developed in order to optimize the therapeutic profile of VD. This report presents a novel experimental system that may help in the understanding of the structural basis for the high potency of a VD analogue like KH1060, which is a 20-epi-22-oxa-derivative of VD. In human breast cancer cells, MCF-7, the half-maximal gene activation values for KH1060 and seven of its structural precursors were determined on a DR3-type VD response element. These eight analogues cover conservative structural changes from 20-epi-VD (MC1288) to KH1060. With a modified version of the limited protease digestion assay the functional affinity of the analogues to VDR was measured. The functional receptor affinity of the eight analogues was found to be directly proportional to their potency in VDR-RXR-mediated gene activity.

Binding Sites↗
PubMed1996

Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cis-retinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells.

All-trans retinoic acid (RA) is the first highly effective differentiation-inducing agent for remission induction in patients with acute promyelocytic leukemia. However, remissions are short-lived because the treatment fails to induce complete differentiation and fails to eradicate the malignant clone. To eliminate rapidly the malignant clone, in analogy with aggressive chemotherapy, the combination of potent differentiation- and apoptosis-inducing drugs working through different receptors and signal pathways may be useful. The active form of vitamin D3 (1,25-dihydroxyvitamin D3; 1,25(OH)2D3) inhibits proliferation and induces differentiation of myeloid leukemic cells. The 9-cis-RA, unlike all-trans-RA which binds only retinoic acid receptors, is a high affinity ligand for both retinoic acid receptors and retinoid X receptors. The aim of this study was to evaluate the therapeutic potential of combining a vitamin D(3) analogue, 20-epi-22-oxa-24a,26a,27a-tri-homo-1alpha,25(OH) 2D, (KH 1060), which belongs to the family of potent 20-epi-1,25(OH),D3 analogues, with 9-cis-RA by assessing their effects on the proliferation, differentiation, and apoptosis of the human leukemia cell line HL-60 in vitro. Our data show that KH 1060 alone is a very potent inhibitor of clonal proliferation of HL-60, but this effect is reversible, and that 9-cis-RA alone is a weak inhibitor of clonal proliferation of HL-60 cells. In contrast, the combination of KH 1060 and 9-cis-RA synergistically and irreversibly inhibited the clonal proliferation of HL-60 cells and induced apoptosis, as detected by morphological changes and DNA fragmentation. This combination also affected the expression of apoptosis-related genes. The bcl-2 protein became nearly undetectable, and expression of bax protein increased slightly (the bax:bcl-2 ratio was 14-fold higher than in untreated cells). Differentiation of treated HL-60 cells was assessed by their ability to produce superoxide, as measured by reduction of nitro blue tetrazolium, positive staining for alpha-naphthyl acetate esterase, phagocytosis, morphology, and analysis of membrane-bound differentiation markers with two-color immunofluorescence. Treatment with the combination of KH 1060 and 9-cis-RA was a potent inducer of differentiation of HL-60, with the cells developing a myelomonocytic phenotype. In summary, our data demonstrate that the combination of both KH 1060 and 9-cis-RA irreversibly and synergistically inhibited clonal growth, induced differentiation and apoptosis of HL-60 cells concomitantly with a very marked decreased expression of bcl-2, and increased the bax:bcl-2 ratio. This drug combination may have important therapeutic significance.

Antigens, Surface↗
PubMed1996

Cytotoxic effects of 1 alpha,25-dihydroxyvitamin D3 and synthetic vitamin D3 analogues on a glioma cell line.

1 alpha,25-Dihydroxyvitamin D3 (1 alpha,25(OH)2D3) has recently been reported to exert a toxic effect on both rat and human glioma cell lines. However the potential clinical use of 1 alpha,25(OH)2D3 in the treatment of glioma is impaired by its potent hypercalcemic effects. We have therefore investigated the effects on glioma cell growth of several vitamin D3 analogues which have previously been shown to be less calcemic in vivo than 1 alpha,25(OH)2D3. The present study shows that several analogues are able to induce, in vitro, the death of rat glioma cells (C6.9). The compound KH 1060 appears to be the most effective in the induction of cell death, while MC 1288 and CB 1093 are as potent as 1 alpha,25(OH)2D3. EB 1089 was somewhat less effective than 1 alpha,25(OH)2D3 and MC 903, which is currently used in the treatment of psoriasis, has only a weak activity on C6.9 cells. The effective doses used are around 10(-9) M for 1 alpha,25(OH)2D3 and 10(-10) M for KH 1060. Interestingly, the toxic effect exerted by 1 alpha,25(OH)2D3 and its analogues is accompanied by several of the biochemical features of apoptosis, such as DNA fragmentation and induction of the c-myc protooncogene. These findings, together with the fact that the therapies currently available for glioma are only palliative, suggest that 1 alpha,25(OH)2D3 analogues such as KH 1060, EB 1089 or CB 1093, alone or in combination with other therapeutic approaches, could be of potential interest in the treatment of brain glial tumors.

Animals↗
PubMed1996

Effect of a vitamin D3 analog, EB1089, on hematopoietic stem cells from normal and myeloid leukemic blasts.

The seco-steroid 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) induces differentiation and inhibits clonal proliferation of HL-60 cells. We analyzed the effect of a novel vitamin D3 analog, EB1089, on normal myeloid and leukemic cells as well as CD34+ cells. EB1089 showed an extraordinary inhibition of clonal growth of HL-60 cells (ED50 = 5 x 10(-11) M) and AML blast cells (ED50 = 9 x 10(-10) M) compared to 1,25(OH)2D3 without suppression of growth of normal human bone marrow CFU-GM. The CD34+ cells from acute myeloid leukemia (AML) blasts were inhibited in a dose-dependent fashion by 1,25(OH)2D3 with an ED50 of 1.2 x 10(-9) M; and even more strikingly, 10(-10) M of EB1089 inhibited all clonal growth of human CD34+ leukemic colony-forming cells. In contrast, both EB1089 and 1,25(OH)2D3 (10(-8) M) showed little or only mild inhibition of CD34+ clongenic hematopoietic cells from normal human peripheral blood (PB); and in liquid culture, EB1089 stimulated the proliferation of normal human CD34+ cells about 2.5 times as compared to control cultures. In order to evaluate the potential use of EB1089 for purging leukemic cells from normal CD34+ progenitor cells for PB stem cell transplantation (PBSCT), normal human PB mononuclear cells (PBMNC) were contaminated with HL-60 cells, and then CD34+ cells purified and treated with EB1089. We found that CD34+ purification and EB1089 purging was able to eliminate approximately 100% of HL-60 leukemic cells with no toxicity to normal CD34+ hematopoietic progenitor cells. These data suggested that purification of CD34+ cells and ex vivo treatment with EB1089 might provide an effective therapeutic approach for PBSCT.

Antigens, CD34↗
PubMed1996

The anti-proliferative and differentiation-inducing effects of vitamin D analogs are not determined by the binding affinity for the vitamin D receptor alone.

Calcipotriol, a synthetic analog of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25[OH]2D3), is used in the treatment of psoriasis. In this investigation, the biological profile of calcipotriol and of two new vitamin D analogs, EB 1213 and GS 1500, has been studied and compared with the profile of 1 alpha,25(OH)2D3. Despite the fact that the affinity for the intracellular vitamin D receptor of the three analogs is comparable (EB 1213) or lower (GS 1500, calcipotriol) than that of 1 alpha,25(OH)2D3, they were all found to be more potent in inhibiting human skin cell proliferation in vitro. The anti-proliferative effect was accompanied by a change in the cytokeratin pattern of the skin cells, indicating a differentiation-inducing effect of the compounds similar to that of 1 alpha,25(OH)2D3. Further investigations including ligand-induced vitamin D receptor transcription studies in chloramphenicol acetyl transferase assays showed that EB 1213 and GS 1500 were more efficient than 1 alpha,25(OH)2D3 in inducing vitamin D receptor transcription. This strongly indicates that not only the binding affinity for the receptor, but more importantly, the ability of the compounds to induce vitamin D receptor transcription, is a determinant of the biological activity of the compounds.

Binding Sites↗
PubMed1996

Vitamin D analogs affect the uptake and metabolism of retinol by human epidermal keratinocytes in culture.

Human epidermis utilizes retinol as precursor for local production of a range of bioactive vitamin A metabolites including 3,4-didehydroretinol, retinoic acid, and 3,4-didehydroretinoic acid. These endogenously formed retinoids bind to nuclear retinoic acid receptors (RARs), thereby altering gene transcription. Because 9-cis-retinoic acid receptors (RXRs) form heterodimers both with RARs and the vitamin D3 receptor (VDR), it is plausible that vitamin D3 may affect retinol metabolism if altered transcription is involved in the regulation of vitamin A-metabolizing enzymes. To investigate the potential effect of vitamin D on retinol metabolism in human skin keratinocytes, HaCaT cells were preincubated with various vitamin D3-analogs at 10(-7)M for 24 h followed by the addition of [3H]retinol for another 24 h period. The uptake and metabolism of the radioactive tracer was monitored by HPLC-radiochromatography. It was found that all synthetic vitamin D-analogs tested (MC903, KH1060, EB1089, and EB1213) reduced the amount of cell-associated [3H]retinoid activity by 35-50% as compared to the vehicle. More specifically, the appearance of the parent substrate and two of its main metabolites, e.g., 3,4-didehydroretinol (ddROH) and 3,4-didehydroretinoic acid (ddRA), was inhibited by the synthetic vitamin D-analogs. The effects on retinol metabolism were not potentiated by coincubation of cells with vitamin D-analogs plus retinoic acid (RA) or 9-cis-RA. This study demonstrates that synthetic vitamin D3 interferes with both the uptake and the metabolism of retinol by human epidermal keratinocytes. Whether the effects are due to direct inhibition of cellular retinol uptake and metabolism or involve VDR-mediated transcriptional alteration of vitamin A metabolizing enzymes remains to be clarified.

Cells, Cultured↗
PubMed1996

Toxicity of 1,25-dihydroxyvitamin D3, tacalcitol, and calcipotriol after topical treatment in rats.

To investigate and compare the effects on calcium metabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogs tacalcitol and calcipotriol after topical treatment, we treated groups of rats topically once daily with three dose levels of each test compound in a vehicle of propylene glycol plus ethanol for 28 d. The urinary calcium excretion was measured after 14 d, and serum calcium and parathyroid hormone were measured at termination. The rats were autopsied, and the kidneys were examined microscopically for mineralizations. Based on the urinary calcium excretion and the serum calcium level, calcipotriol was found to be 60 times less calcemic, and tacalcitol was slightly less calcemic, than 1,25(OH)2D3 after repeated topical application to rats. Serum parathyroid hormone was suppressed to a lower degree by calcipotriol and tacalcitol than by 1,25(OH)2D3, and the incidence and severity of renal corticomedullary mineralization were higher in rats treated with 1,25(OH)2D3 and tacalcitol than with calcipotriol. We conclude that calcipotriol is much less calcemic than 1,25(OH)2D3 or tacalcitol when applied topically to rats in a vehicle that enhances penetration into the skin. We attribute the lower calcemic effect of calcipotriol to the pharmacokinetic profile of the compound, particularly its rapid metabolization into inactive compounds.

Administration, Topical↗
PubMed1995

The anti-proliferative effect of vitamin D3 analogues is not mediated by inhibition of the AP-1 pathway, but may be related to promoter selectivity.

The hormone 1,25-dihydroxyvitamin D3 (VD) is able to induce cellular differentiation and to inhibit cellular proliferation, which provides it with an interesting therapeutic potential in cancer. However, side effects of VD on homeostasis (eg hypercalcemia) had made the need for the development of VD analogues with low calcemic effect. On the human breast cancer cell line MCF-7 we obtained with the VD analogue EB1089 an about 100-fold higher anti-proliferative effect than with VD. We found that this difference in biological activity is neither related to increased functional affinity to the VD receptor nor to repression of AP-1 activity. The physiologically most prominent complex of the VD receptor is a heterodimer with the retinoid X receptor that binds VD response elements formed two hexameric core binding motifs being arranged either as direct repeats spaced by 3 nucleotides (DR3s) or as inverted palindromes spaced by 9 nucleotides (IP9s). We observed that EB1089 stimulates transcriptional activation from IP9-type elements at clearly lower concentrations than from DR3-type elements. It is possible that IP9-type response elements play an important role in or contribute to the control of cell proliferation, so that promoter-selectivity may explain the high anti-proliferative effect of EB1089.

Antineoplastic Agents↗
PubMed1995

20-epi-vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines.

We have studied the in vitro biological activities and mechanism of action of 1,25-dihydroxyvitamin D3 (1,25D3) and four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; and 1,25(OH)2-16ene-23yne-D3] on proliferation and differentiation of estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, and MDA-MB-231), estrogen receptor-weakly positive (BT474), and estrogen receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was the most potent analogue, because it was able to induce differentiation in all seven breast cancer cell lines (measured by lipid staining) and to suppress more than 50% clonal proliferation (ED50) at 10(-10) M in all cell lines, except MDA-MB-436 and BT-20. To explore how these compounds mediated antiproliferative actions, their effects on the cell cycle, on expression of bcl-2 and p53, and on apoptosis were assessed. Five of six cell lines have a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining showed that the p53 protein was predominantly localized in the nucleus in each of the breast cancer cell lines except for MCF-7, which expressed the protein predominantly in the cytoplasm. After incubation with KH 1060 (3 days; 10(-7) M), expression of bcl-2 protein as determined by immunohistochemical localization was markedly decreased in BT-474, MCF-7, and MDA-MB-231; these same cells were profoundly inhibited in their clonal proliferation and arrested in the G0/G1 phase of the cell cycle when cultured with KH 1060. In contrast, BT-20 and MDA-MB-436 cells that were refractory to the antiproliferative effect of KH 1060 (ED50 < 10(-6) M) had no down-regulation of their bcl-2 expression and no cell cycle changes after exposure to KH 1060. MCF-7 showed morphological changes and DNA fragmentation, indicative of apoptosis after 48 h incubation with KH 1060 (10(-6) M), during which time p53 protein accumulated in the nucleus and decreased in the cytoplasm. In contrast, no apoptosis was detected in three other breast lines (MDA-MB-231, SK-BR-3, and BT-474) that had a mutated p53. In conclusion, the data indicate that KH 1060 is an extremely potent 1,25D3 analogue inducing differentiation of all six breast cancer lines and potently inhibiting clonal growth of four of them with concomitant decreased bcl-2 and cell cycle arrest at G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)

Apoptosis↗
PubMed1995

Vitamin D3 analogs: effect on leukemic clonal growth and differentiation, and on serum calcium levels.

In vitro, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) induces differentiation of HL-60 cells and inhibits their proliferation as well as the proliferation of leukemic cells from patients. In vivo, the survival of mice challenged with syngeneic leukemic cells is enhanced by treatment with 1,25(OH)2D3. Patients treated with 1,25(OH)2D3 develop hypercalcemia at a serum level of 2 x 10(-10) mol/l which is a concentration too low to achieve an antileukemic effect in vitro. Several interesting vitamin D3 analogs have recently been developed. We initially examined the effect of 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 and 24a,26a,27a-tri-homo-22,24-diene-1-alpha,25-(OH)2-D3 on clonal growth and differentiation of HL-60 cells. Each of the analogs had comparable effects on clonal growth with 50% inhibition (ED50) at concentrations of 0.2-0.5 x 10(-9) M; 1,25(OH)2D3 was about 20- to 50-fold less active in inhibiting growth. Differentiation was determined by induction of superoxide production, as measured by nitroblue tetrazolium (NBT) reduction and by expression of a macrophage-specific enzyme (alpha napthyl acetate esterase (ANAE)). The 24a,26a,27a-tri-homo-22,24-diene-1-alpha,25-(OH)2-D3 and 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 were about 5- to 14-fold more potent than 1,25(OH)2D3. The hypercalcemia inducing side-effects of these analogs and three other previously identified, extremely potent vitamin D3 compounds, as well as 1,25(OH)2D3, were studied. The analogs were administered intraperitoneally every other day (qod) for 5 weeks; serum was collected weekly and Ca2+ measured by atomic absorption spectrophotometry. The highest tolerated dose of each analog leaving all mice alive was for 1,25(OH)2D3: 0.25 micrograms; 1,25(OH)2-24a,26a,27a-tri-homo-22,24-diene-D3: 0.25 micrograms; and 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3: 0.0625 micrograms. Another hexafluoro compound with potent abilities to induce differentiation (1,25(OH)2-16ene-23yne-26,27-F6-D3) was very toxic, all mice died in the second week while receiving 0.0625 micrograms qod. Prior studies showed that the most potent compound in inducing differentiation of HL-60 was 1,25(OH)2-20-epi-D3; but it is very toxic as only one mouse survived a dose of > or = 0.0125 micrograms qod for 5 weeks. 1,25(OH)2-16ene-23yne-D3 is an extremely active inducer of differentiation but, on the other hand, it has low potential to produce hypercalcemia; mice maintained normal serum calcium levels even while receiving 2 micrograms qod for 5 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

The effects of combined treatment with the novel vitamin D analogue MC 1288 and cyclosporine A on cardiac allograft survival.

The efficacy of combined treatment with the novel vitamin D analogue MC 1288 (20-epi-1 alpha,25-dihydroxycholecalciferol) and cyclosporine A (CyA) in preventing rejection following organ transplantation was evaluated in the heterotopic cardiac allograft model. Wistar/Kyoto rats received hearts from PVG donors and were subsequently treated with MC 1288 and CyA in various dose combinations. Administration of MC 1288 0.1 microgram/kg together with CyA 5 mg/kg produced significantly prolonged graft survival times as compared with single therapy with MC 1288 0.1 microgram/kg (p < 0.01) or CyA 5 mg/kg (p < 0.001). MC 1288 and CyA were tested also in combination with the immunomodulating drug LS-2616, which, in several laboratories, is used as a model for the evaluation of new combinations of immunosuppressive drugs. LS-2616 abolishes the immunosuppressive effect of CyA and the transplanted hearts are thus rejected at the same time as grafts of untreated recipients, i.e. on day 8. The immunosuppressive effect of MC 1288 is also counteracted by LS-2616, but the effect is not absolute and the median graft survival time is 11.0 days. Combined treatment with MC 1288 and CyA in the presence of LS-2616 resulted in a median graft survival time of 14.0 days. The results obtained in our experiments indicate at least an additive effect of MC 1288 and CyA thus suggesting that in the future MC 1288, or other vitamin D analogues, might be used to control rejection, either alone, in combination with CyA or in combination with other immunosuppressive drugs with other mechanisms of action.

Adjuvants, Immunologic↗